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Abstract
Common inflammatome gene signatures as well as disease-specific signatures were identified by analyzing 12 expression profiling data sets derived from 9 different tissues isolated from 11 rodent inflammatory disease models. The inflammatome signature significantly overlaps with known drug targets and co-expressed gene modules linked to metabolic disorders and cancer. A large proportion of genes in this signature are tightly connected in tissue-specific Bayesian networks (BNs) built from multiple independent mouse and human cohorts. Both the inflammatome signature and the corresponding consensus BNs are highly enriched for immune response-related genes supported as causal for adiposity, adipokine, diabetes, aortic lesion, bone, muscle, and cholesterol traits, suggesting the causal nature of the inflammatome for a variety of diseases. Integration of this inflammatome signature with the BNs uncovered 151 key drivers that appeared to be more biologically important than the non-drivers in terms of their impact on disease phenotypes. The identification of this inflammatome signature, its network architecture, and key drivers not only highlights the shared etiology but also pinpoints potential targets for intervention of various common diseases.
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Details
1 Informatics and Analysis, Merck Research Laboratories, Merck & Co., Inc., West Point, PA, USA
2 Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA; Institute of Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, NY, USA; Graduate School of Biological Sciences, Mount Sinai School of Medicine, New York, NY, USA; Sage Bionetworks, Seattle, WA, USA
3 Sage Bionetworks, Seattle, WA, USA; Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA
4 Covance Genomics Laboratory, Seattle, WA, USA
5 Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA
6 Sage Bionetworks, Seattle, WA, USA
7 Investigative Toxicology Department, Amgen, Seattle, WA, USA
8 Systems Immunology, Benaroya Research Institute, Seattle, WA, USA
9 Department of Respiratory and Inflammation, Merck Research Laboratories, Merck & Co., Inc., Boston, MA, USA
10 In Vivo Pharmacology, Merck Research Laboratories, Merck & Co., Inc., Boston, MA, USA
11 In Vivo Pharmacology, Merck Research Laboratories, Merck & Co., Inc., Kenilworth, NJ, USA
12 Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, USA
13 External Scientific Affairs, Merck Research Laboratories, Merck & Co., Inc., Rahway, NJ, USA
14 World Wide Regulatory Affairs, Merck Research Laboratories, Merck & Co., Inc., Rahway, NJ, USA
15 Product, Ayasdi Inc., Palo Alto, CA, USA
16 Oncology Research Unit, Pfizer, San Diego, CA, USA
17 Genomics Platform, Broad Institute, Cambridge, MA, USA
18 Department of Respiratory and Inflammation, Merck Research Laboratories, Merck & Co., Inc., Rahway, NJ, USA
19 Informatics and Analysis, Merck Research Laboratories, Merck & Co., Inc., Boston, MA, USA